The objective of this proposal is the study of the pharmacology and toxicology of the endothelial cell membrane in the lung. This membrane has a number of important biochemical functions, and the enzymes and transport sites mediating these functions are exposed to toxins and drugs in the circulation, and are vulnerable to changes in blood chemistry. Due to its location, the pulmonary endothelial cell is uniquely susceptible to damage. Damage can have sequelae ranging far beyond the endothelium. Impaired ability to clear microthrombi, or capillary occlusion due to endothelial proliferation, may lead to pulmonary arterial hypertension, and damage to the right heart, in addition to insufficient flow to the left heart. Impairment of endothelial function may also result in spillover of vasoactive substances into the systemic circulation, or disturbance in regulation of the renin-angiotensin system. Our objective is to select endothelial functions that may be measured in the isolated perfused lung. We wish to develop tools for the specific inhibition of each function. These studies are designed to give insight on the selective toxicity of the pulmonary endothelial cell, and to reveal how drugs, disease, or other environmental alterations affect endothelial cell function.